Apoptosis, or programmed cell death, is a naturally occurring process that has been strongly conserved during evolution to prevent uncontrolled cell proliferation. This form of cell suicide plays a crucial role in the development and maintenance of multicellular organisms by eliminating superfluous or unwanted cells. However, if this process goes awry, excessive apoptosis can result in cell loss and degenerative disorders, while insufficient apoptosis contributes to the development of cancer, autoimmune disorders and viral infections (Thompson, Science, 1995, 267, 1456-1462).
Although several stimuli can induce apoptosis, little is known about the intermediate signaling events, including inhibition, that connect the cell death stimuli to a common cell death pathway conserved across many species. Recently, a family of apoptosis inhibitor proteins homologous to those produced by viruses has been identified in humans.
Cellular Inhibitor of Apoptosis-2 (also known as c-IAP-2, apoptosis inhibitor 2, API-2, hIAP-1, and MIHC) is a member of the inhibitor of apoptosis (IAP) family of anti-apoptotic proteins which interfere with the transmission of intracellular death signals. Cellular Inhibitor of Apoptosis-2 mRNA expression is most abundant in thymus and spleen (Rothe et al., Cell, 1995, 83, 1243-1252). It was first cloned and characterized as a component of the TNFR2-TRAF signaling pathway (Rothe et al., Cell, 1994, 78, 681-692) and was shown to be recruited to the cytoplasmic domain of TNFR2 in association with a TRAF2-TRAF1 heterocomplex (Rothe et al., Cell, 1995, 83, 1243-1252). Later it was identified as a factor that could inhibit apoptosis caused by the overexpression of interleukin 1 beta converting enzyme (ICE) or caspase-1, a protease required for apoptosis in mammals (Uren et al., Proc. Natl. Acad. Sci. U S A, 1996, 93, 4974-4978). Subsequently, it has been shown that Cellular Inhibitor of Apoptosis-2 inhibits other cell death proteases, namely caspase-3, caspase-7 and caspase-8 (Deveraux et al., Embo J., 1998, 17, 2215-2223; Roy et al., Embo J., 1997, 16, 6914-6925; Wang et al., Science, 1998, 281, 1680-1683).
Overexpression of Cellular Inhibitor of Apoptosis-2 was shown to activate NF kappa B and suppress TNF cytotoxicity in mammalian cells. However, a mutant form of the protein lacking the C-terminal end inhibits NF kappa B and enhances TNF cytotoxicity (Chu et al., Proc. Natl. Acad. Sci. U S A, 1997, 94, 10057-10062) suggesting a critical role for Cellular Inhibitor of Apoptosis-2 in cell survival.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of Cellular Inhibitor of Apoptosis-2.
To date, strategies aimed at inhibiting Cellular Inhibitor of Apoptosis-2 function have involved the use of molecules that block upstream entities including the TRAF2-TRAF1 heterocomplex and mutations of the Cellular Inhibitor of Apoptosis-2 protein itself. However, these strategies are untested as therapeutic protocols as well as being non-specific to Cellular Inhibitor of Apoptosis-2, as many divergent pathways arise from TNF signaling. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting Cellular Inhibitor of Apoptosis-2 function. It is therefore believed that antisense oligonucleotides will provide a promising new pharmaceutical tool for the effective and specific modulation of Cellular Inhibitor of Apoptosis-2 expression.